tbuckley/cabot-search huggingface dataset:
Metformin improves cancer immunotherapy by directly rescuing tumor-infiltrating CD8 T lymphocytes from hypoxia-induced immunosuppression
Authors: Veronica Finisguerra, Tereza Dvorakova, Matteo Formenti, Pierre Van Meerbeeck, Lionel Mignion, Bernard Gallez, Benoit J Van den Eynde
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Despite their revolutionary success in cancer treatment over the last decades, immunotherapies encounter limitations in certain tumor types and patients. The efficacy of immunotherapies depends on tumor antigen-specific CD8 T-cell viability and functionality within the immunosuppressive tumor microenvironment, where oxygen levels are often low. Hypoxia can reduce CD8 T-cell fitness in several ways and CD8 T cells are mostly excluded from hypoxic tumor regions. Given the challenges to achieve durable reduction of hypoxia in the clinic, ameliorating CD8 T-cell survival and effector function in hypoxic condition could improve tumor response to immunotherapies. Methods Activated CD8 T cells were exposed to hypoxia and metformin and analyzed by fluorescence-activated cell sorting for cell proliferation, apoptosis and phenotype. In vivo, metformin was administered to mice bearing hypoxic tumors and receiving either adoptive cell therapy with tumor-specific CD8 T cells, or immune checkpoint inhibitors; tumor growth was followed over time and CD8 T-cell infiltration, survival and localization in normoxic or hypoxic tumor regions were assessed by flow cytometry and immunofluorescence. Tumor oxygenation and hypoxia were measured by electron paramagnetic resonance and pimonidazole staining, respectively. Results We found that the antidiabetic drug metformin directly improved CD8 T-cell fitness in hypoxia, both in vitro and in vivo. Metformin rescued murine and human CD8 T cells from hypoxia-induced apoptosis and increased their proliferation and cytokine production, while blunting the upregulation of programmed cell death protein 1 and lymphocyte-activation gene 3. This appeared to result from a reduced production of reactive oxygen species, due to the inhibition of mitochondrial complex I. Differently from what others reported, metformin did not reduce tumor hypoxia, but rather increased CD8 T-cell infiltration and survival in hypoxic tumor areas, and synergized with cyclophosphamide to enhance tumor response to adoptive cell therapy or immune checkpoint blockade in different tumor models. Conclusions This study describes a novel mechanism of action of metformin and presents a promising strategy to achieve immune rejection in hypoxic and immunosuppressive tumors, which would otherwise be resistant to immunotherapy.
OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs
Authors: Ning Yang, Yi Wang, Shuaitong Liu, Shanza Baseer Tariq, Joseph M. Luna, Gregory Mazo, Adrian Tan, Tuo Zhang, Jiahu Wang, Wei Yan, John Choi, Anthony Rossi, Jenny Zhaoying Xiang, Charles M. Rice, Taha Merghoub, Jedd D. Wolchok, Liang Deng
Journal: The Journal of Experimental Medicine (2023)

Effective depletion of immune suppressive regulatory T cells (Tregs) in the tumor microenvironment without triggering systemic autoimmunity is an important strategy for cancer immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus with a long history of human use. Here, we report rational engineering of an immune-activating recombinant MVA (rMVA, MVA∆E5R-Flt3L-OX40L) with deletion of the vaccinia E5R gene (encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase, cGAS) and expression of two membrane-anchored transgenes, Flt3L and OX40L. Intratumoral (IT) delivery of rMVA (MVA∆E5R-Flt3L-OX40L) generates potent antitumor immunity, dependent on CD8+ T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and type I IFN signaling. Remarkably, IT rMVA (MVA∆E5R-Flt3L-OX40L) depletes OX40hi regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Single-cell RNA-seq analyses of tumors treated with rMVA showed the depletion of OX40hiCCR8hi Tregs and expansion of IFN-responsive Tregs. Taken together, our study provides a proof-of-concept for depleting and reprogramming intratumoral Tregs via an immune-activating rMVA.
Learning curves in laparoscopic distal pancreatectomy: a different experience for each generation
Authors: Tess M.E. van Ramshorst, Bjørn Edwin, Ho-Seong Han, Masafumi Nakamura, Yoo-Seok Yoon, Takao Ohtsuka, Tore Tholfsen, Marc G. Besselink, Mohammad Abu Hilal
Journal: International Journal of Surgery (2023)

Learning curves of laparoscopic distal pancreatectomy (LDP) are mostly based on 'self-taught' surgeons who acquired sufficient proficiency largely through self-teaching. No learning curves have been investigated for 'trained' surgeons who received training and built on the experience of the 'self-taught' surgeons. This study compared the learning curves and outcome of LDP between 'self-taught' and 'trained' surgeons in terms of feasibility and proficiency using short-term outcomes.
Acute exacerbation of fibrotic interstitial lung disease beyond idiopathic pulmonary fibrosis: time to intervene
Authors: Ryoko Egashira, Ganesh Raghu
Journal: European Respiratory Journal (2023)

<b>Well-designed multicentre clinical trials are warranted to determine a safe and efficacious treatment regimen for patients with acute exacerbation of IPF and fibrotic lung disease beyond IPF</b>http://bit.ly/3KnaHtV
Mechanism of Tumor-Platelet Communications in Cancer
Authors: Tejasvi Dudiki, Manoj Veleeparambil, Irina Zhevlakova, Sudipta Biswas, Eric A. Klein, Peter Ford, Eugene A. Podrez, Tatiana V. Byzova
Journal: Circulation Research (2023)

Thrombosis is one of the main complications in cancer patients often leading to mortality. However, the mechanisms underlying platelet hyperactivation are poorly understood.
The art of clinical trial design in pulmonary fibrosis
Authors: Jürgen Behr
Journal: European Respiratory Journal (2023)

The design of clinical trials is an art on its own. There are numerous, partially conflicting aspects a clinical trial has to satisfy. First and most importantly, the trial, especially in phase III trials, should ideally demonstrate a statistically significant effect of the drug under investigation on a clinically relevant primary endpoint. To accomplish this task, several aspects need to be considered. A crucial aspect at this stage is the expected effect size of the drug and the known variation of the primary endpoint measure, which together govern the power calculation and the sample size needed. As any treatment effect will need time to develop, time is also an important component: if the study is too short important effects or relevant but rare adverse events may be missed; if the study is too long patient retention may be difficult and dropouts may lead to missing data. A realistic estimate of the expected treatment effect on the primary endpoint and a sound power calculation are the mainstay of a successful study. Eligibility criteria for clinical trials need critical consideration <https://bit.ly/3mWl8Lz>
Improvement of air quality has a positive impact on lung growth, particularly during puberty
Authors: Anke Hüls
Journal: European Respiratory Journal (2023)

<b>Improving air quality has a positive impact on lung growth, particularly during puberty. We need studies to address the impact of co-exposure to air pollutants and PM<sub>2.5</sub>, and in lower-income countries with higher burden of childhood respiratory illness.</b>https://bit.ly/3YTiFyW
Minimum inhibitory concentrations and sequencing data have to be analysed in more detail to set provisional epidemiological cut-off values for<i>Mycobacterium tuberculosis</i>complex
Authors: Claudio U. Köser, Florian P. Maurer
Journal: European Respiratory Journal (2023)

There is a clear need for a high-quality broth microdilution (BMD) assay for quantitative antimicrobial susceptibility testing (AST) for the Mycobacterium tuberculosis complex (MTBC) [1]. The BMD plate developed by the CRyPTIC Consortium, therefore, represents an important advance [2]. However, the analysis of the resulting data has several limitations. Provisional epidemiological cut-off values for M. tuberculosis complex need to be set carefully <http://bit.ly/3XjJ8px> C.U. Köser is a visiting scientist at the Department of Genetics, University of Cambridge, and research associate at Wolfson College, University of Cambridge. Feedback from G. Kahlmeter, T. Schön and J. Turnidge was gratefully received. We thank L. Sonnenkalb for clarifications regarding her work.
The determination of epidemiological cut-off values requires a systematic and joint approach based on quality controlled, non-truncated minimum inhibitory concentration series
Authors: Gunnar Kahlmeter, John Turnidge
Journal: European Respiratory Journal (2023)

<b>The determination of epidemiological cut-off values (ECOFFs) requires a systematic and joint approach based on quality controlled, non-truncated minimum inhibitory concentration series</b> https://bit.ly/3DD0F47
Theranostics applications of quantum dots in regenerative medicine, cancer medicine, and infectious diseases
Authors: Hiroshi Yukawa, Kazuhide Sato, Yoshinobu Baba
Journal: Advanced Drug Delivery Reviews (2023)

Quantum dots (QDs) have attracted attention for their application and commercialization in all industrial fields, including communications, displays, and solar cells, due to their excellent optical properties based on the quantum size effect. In recent years, the development of QDs that do not contain cadmium which is toxic to cells and living organisms, has progressed, and they have attracted considerable attention in the bio-imaging field for targeting molecules and cells. Furthermore, recently, the need for diagnostics and treatment at the single molecule and single cell level in the medical field has been increasing, and the application of QDs in the medical field is also accelerating. Therefore, this paper outlines the frontiers of diagnostic and therapeutic applications (theranostics) of QDs, especially in advanced medical fields such as regenerative medicine, oncology, and infectious diseases.
Bioactive phytocompounds for oral cancer prevention and treatment: A comprehensive and critical evaluation
Authors: Jack T. Burcher, Lindsay K. DeLiberto, Andrea M. Allen, Kaitlyn L. Kilpatrick, Anupam Bishayee
Journal: Medicinal Research Reviews (2023)

Abstract The high incidence of oral cancer combined with excessive treatment cost underscores the need for novel oral cancer preventive and therapeutic options. The value of natural agents, including plant secondary metabolites (phytochemicals), in preventing carcinogenesis and representing expansive source of anticancer drugs have been established. While fragmentary research data are available on antioral cancer effects of phytochemicals, a comprehensive and critical evaluation of the potential of these agents for the prevention and intervention of human oral malignancies has not been conducted according to our knowledge. This study presents a complete and critical analysis of current preclinical and clinical results on the prevention and treatment of oral cancer using phytochemicals. Our in‐depth analysis highlights anticancer effects of various phytochemicals, such as phenolics, terpenoids, alkaloids, and sulfur‐containing compounds, against numerous oral cancer cells and/or in vivo oral cancer models by antiproliferative, proapoptotic, cell cycle‐regulatory, antiinvasive, antiangiogenic, and antimetastatic effects. Bioactive phytochemicals exert their antineoplastic effects by modulating various signaling pathways, specifically involving the epidermal growth factor receptor, cytokine receptors, toll‐like receptors, and tumor necrosis factor receptor and consequently alter the expression of downstream genes and proteins. Interestingly, phytochemicals demonstrate encouraging effects in clinical trials, such as reduction of oral lesion size, cell growth, pain score, and development of new lesions. While most phytochemicals displayed minimal toxicity, concerns with bioavailability may limit their clinical application. Future directions for research include more in‐depth mechanistic in vivo studies, administration of phytochemicals using novel formulations, investigation of phytocompounds as adjuvants to conventional treatment, and randomized clinical trials.
Reply to Alireza Ghoreifi and Hooman Djaladat’s Letter to the Editor re: Daniel D. Shapiro, Jose A. Karam, Logan Zemp, et al. Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Therapy Is Safe and Facilitates Treatment-free Intervals. Eur Urol Open Sci 2023;50:43–6
Authors: Daniel D. Shapiro, Jose A. Karam, Viraj A. Master, Logan W. Zemp, Wade J. Sexton, Surena F. Matin, Philippe E. Spiess, E. Jason Abel
Journal: European Urology (2023)
3D Printing of Collagen Scaffold with Enhanced Resolution in a Citrate‐Modulated Gellan Gum Microgel Bath
Authors: Zheng‐Tian Xie, Jinfeng Zeng, Dong‐Hee Kang, Shigeyoshi Saito, Shigeru Miyagawa, Yoshiki Sawa, Michiya Matsusaki
Journal: Advanced Healthcare Materials (2023)

3D printing in a microgel-based supporting bath enables the construction of complex structures with soft and watery biomaterials but the low print resolution is usually an obstacle to its practical application in tissue engineering. Herein, high-resolution printing of a 3D collagen organ scaffold is realized by using an engineered Gellan gum (GG) microgel bath containing trisodium citrate (TSC). The introduction of TSC into the bath system not only mitigates the aggregation of GG microgels, leading to a more homogeneous bath morphology but also suppresses the diffusion of the collagen ink in the bath due to the dehydration effect of TSC, both of which contribute to the improvement of print resolution. 3D collagen organ structures such as hand, ear, and heart are successfully constructed with high shape fidelity in the developed bath. After printing, the GG and TSC can be easily removed by washing with water, and the obtained collagen product exhibits good cell affinity in a tissue scaffold application. This work offers an easy-to-operate strategy for developing a microgel bath for high-resolution printing of collagen, providing an alternative path to in vitro 3D organ construction.
Worst area local Hidradenitis suppurativa Activity and Severity Index-Revised (W-HASI-R): a study evaluating construct validity
Authors: Gretchen Bellefeuille, Briana Paiewonsky, Bisma Khalid, Rebecca L Freese, Michelle A Lowes, Joslyn S Kirby, Afsaneh Alavi, Noah Goldfarb
Journal: British Journal of Dermatology (2023)

Current validated hidradenitis suppurativa (HS) severity assessment tools are time-consuming and impractical in fast-paced, ambulatory clinic settings. This study evaluated the construct validity of the most severe or ‘worst’ area local Hidradenitis suppurativa Activity and Severity Index-Revised (W-HASI-R) as a novel target area assessment tool for clinical setting use. W-HASI-R had strong association with the International Hidradenitis Suppurativa Severity Score System and abscess and nodule count, moderate association with Hurley stage and HS physician global assessment and weak, negative association with reverse-scored Dermatology Quality Life Index. The resulting data suggest that W-HASI-R may be an option as an efficient target area assessment tool for fast-paced, ambulatory settings.
Role of Dickkopf-3 in Blood Pressure Regulation in Mice and Hypertensive Rats
Authors: Carla Letizia Busceti, Albino Carrizzo, Franca Bianchi, Massimiliano De Lucia, Antonio Damato, Chiara Cazzin, Eleonora Venturini, Paola Di Pietro, Roxana Paula Ginerete, Luisa Di Menna, Maria Cotugno, Rosita Stanzione, Simona Marchitti, Serena Migliarino, Michele Ciccarelli, Sebastiano Sciarretta, Valeria Bruno, Giuseppe Battaglia, Francesco Fornai, Massimo Volpe, Speranza Rubattu, Ferdinando Nicoletti, Carmine Vecchione
Journal: Circulation Research (2023)

Dkk3 (Dickkopf-3) is a secreted glycoprotein known for its proapoptotic and angiogenic activity. The role of Dkk3 in cardiovascular homeostasis is largely unknown. Remarkably, the Dkk3 gene maps within a chromosome segment linked to the hypertensive phenotype in spontaneously hypertensive rats (SHR).We used Dkk3-/- mice or stroke-resistant (sr) and stroke-prone (sp) SHR to examine the role of Dkk3 in the central and peripheral regulation of blood pressure (BP). We used lentiviral expression vector to rescue Dkk3 in knockout mice or to induce Dkk3 overexpression or silencing in SHR.Genetic deletion of Dkk3 in mice enhanced BP and impaired endothelium-dependent acetylcholine-induced relaxation of resistance arteries. These alterations were rescued by restoring Dkk3 expression either in the periphery or in the central nervous system (CNS). Dkk3 was required for the constitutive expression of VEGF (vascular endothelium growth factor), and the action of Dkk3 on BP and endothelium-dependent vasorelaxation was mediated by VEGF-stimulated phosphatidylinositol-3-kinase pathway, leading to eNOS (endothelial NO synthase) activation both in resistance arteries and the CNS. The regulatory function of Dkk3 on BP was confirmed in SHR stroke-resistant and SHR stroke-prone in which was blunted in both resistance arteries and brainstem. In SHR stroke-resistant, lentiviral expression vector-induced Dkk3 expression in the CNS largely reduced BP, whereas Dkk3 knock-down further enhanced BP. In SHR stroke-prone challenged with a hypersodic diet, lentiviral expression vector-induced Dkk3 expression in the CNS displayed a substantial antihypertensive effect and delayed the occurrence of stroke.These findings demonstrate that Dkk3 acts as peripheral and central regulator of BP by promoting VEGF expression and activating a VEGF/Akt (protein kinase B)/eNOS hypotensive axis.
Nomogram development and validation for predicting minimally invasive step-up approach failure in infected necrotizing pancreatitis patients: a retrospective cohort study
Authors: Gang Li, Shuai Li, Longxiang Cao, Wenjian Mao, Jing Zhou, Bo Ye, Jingzhu Zhang, Ling Ding, Yin Zhu, Lu Ke, Yuxiu Liu, Zhihui Tong, Weiqin Li
Journal: International Journal of Surgery (2023)

Previous studies have shown that minimally invasive treatment for infected necrotizing pancreatitis (INP) may be safer and more effective than open necrosectomy (ON), but ON is still irreplaceable in a portion of INP patients. Furthermore, there is a lack of tools to identify INP patients at risk of minimally invasive step-up approach failure (eventually received ON or died), which may enable appropriate treatment for them. Our study aims to identify risk factors that can predict minimally invasive step-up approach failure in INP patients and to develop a nomogram for early prediction. Multivariate logistic regression was performed to evaluate the association between minimally invasive step-up approach failure and factors regarding demographics, disease severity, laboratory index, and the location of extrapancreatic necrotic collections. A novel nomogram was developed, and its performance was validated both internally and externally by its discrimination, calibration, and clinical usefulness. There were 267, 89, and 107 patients in the training, internal, and external validation cohorts, respectively. Multivariate logistic regression demonstrated that the computed tomography severity index (CTSI) greater than 8 points, Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 16 points or more, early spontaneous bleeding, fungi infection, granulocyte and platelet decrease within 30 days of acute pancreatitis onset, and extrapancreatic necrosis collection located in small bowel mesentery were independent risk factors for minimally invasive step-up approach failure. The area under the curve and coefficient of determination ( R2 ) of the nomogram constructed from the above factors were 0.920 and 0.644, respectively. The Hosmer-Lemeshow test showed that the model had good fitness ( P =0.206). In addition, the nomogram performed well in both the internal and external validation cohorts. The nomogram had a good performance in predicting minimally invasive step-up approach failure, which may help clinicians distinguish INP patients at risk of minimally invasive step-up approach failure early.
Facilitators of co-leadership for quality care
Authors: Olive Cocoman, Martin Dohlsten, Ernest Konadu Asiedu, Desalegn Bekele Taye, Margaret Mannah, Bongani Chikwapulo, Nana Mensah Abramah, Isabella Sagoe-Moses
Journal: BMJ (2023)

<b>Olive Cocoman and colleagues</b> argue that national leadership for quality of care requires working in a co-leadership model such that quality and programme units have equal standing and clearly defined individual roles and responsibilities
ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma
Authors: Evangeline R. Jackson, Ryan J. Duchatel, Dilana E. Staudt, Mika L. Persson, Abdul Mannan, Sridevi Yadavilli, Sarah Parackal, Shaye Game, Wai Chin Chong, W. Samantha N. Jayasekara, Marion Le Grand, Padraic S. Kearney, Alicia M. Douglas, Izac J. Findlay, Zacary P. Germon, Holly P. McEwen, Tyrone S. Beitaki, Adjanie Patabendige, David A. Skerrett-Byrne, Brett Nixon, Nathan D. Smith, Bryan Day, Neevika Manoharan, Sumanth Nagabushan, Jordan R. Hansford, Dinisha Govender, Geoff B. McCowage, Ron Firestein, Meegan Howlett, Raelene Endersby, Nicholas G. Gottardo, Frank Alvaro, Sebastian M. Waszak, Martin R. Larsen, Yolanda Colino-Sanguino, Fatima Valdes-Mora, Andria Rakotomalala, Samuel Meignan, Eddy Pasquier, Nicolas André, Esther Hulleman, David D. Eisenstat, Nicholas A. Vitanza, Javad Nazarian, Carl Koschmann, Sabine Mueller, Jason E. Cain, Matthew D. Dun
Journal: Cancer Research (2023)

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.